Synthetic Studies on Amide Bond Isosteres and Their Application to Artificial CXCR4 Ligands

2010 Fiscal Year Final Research Report

• Project/Area Number: 21890113
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Drug development chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: NARUMI Tetsuo Tokyo Medical and Dental University, 生体材料工学研究所, 助教 (50547867)
• Project Period (FY): 2009 – 2010
• Keywords: 医薬品化学

Research Abstract

Replacement of the planar amide bond with a surrogate alkene substructure represents a promising approach to overcome their major limitations such as poor bioavailability and short physiological half-life, which limit their medicinal and biological use. However, development of effective ground state isosteric and isoelectronic analogues of the amide bond have yet to be developed. In this study, synthetic methodologies for a newly designed chloroalkene dipeptide isosteres (CADIs) were examined to develop diastereoselective, divergent, and practical synthetic approaches toward (Z)-chlororalkene and (E)-chloroalklene isostere skeletons utilizing organocopper-mediated reactions. These studies should contribute to the development of peptidomimetics-based medicinal chemistry.

Research Products

• [Journal Article] Fluorescence-Quenching Screening of Protein Kinase C Ligands with an Environmentally Sensitive Fluorophore (2011)
  • Author(s): W.Nomura, N.Ohashi, Y.Okuda, T.Narumi, T.Ikura, N.Ito, H.Tamamura, 他
  • Journal Title: Bioconjugate Chem. in press
  • Peer Reviewed
• [Journal Article] Synthetic Caged DAG-lactones for Photochemically-controlled Activation of Protein Kinase C (2011)
  • Author(s): W.Nomura, T.Narumi, N.Ohashi, Y.Serizawa, NE.Lewin, PM.Blumberg, T.Furuta, H.Tamamura, 他
  • Journal Title: ChemBioChem 12巻 Pages: 535-539
  • Peer Reviewed
• [Journal Article] Fluorescent-responsive Synthetic C1b Domains of Protein Kinase Cδ as Reporters of Specific High Affinity Ligand Binding (2011)
  • Author(s): N.Ohashi, W.Nomura, T.Narumi, NE.Lewin, K.Itotani, PM.Blumberg, Hirokazu Tamamura, 他
  • Journal Title: Bioconjugate Chem. 22巻 Pages: 82-87
  • Peer Reviewed
• [Journal Article] Azamacrocyclic-metal Complexes as CXCR4 Antagonists (2011)
  • Author(s): T.Tanaka, T.Narumi, T.Ozaki, A.Sohma, N.Ohashi, C.Hashimoto, K.Itotani, W.Nomura, T.Murakami, N.Yamamoto, H.Tamamura, 他
  • Journal Title: ChemMedChem 6巻 Pages: 834-839
  • Peer Reviewed
• [Journal Article] Bivalent Ligands of CXCR4 with Rigid Linkers for Elucidation of the Dimerization State in Cells (2010)
  • Author(s): T.Tanaka, W.Nomura, T.Narumi, A.Masuda, H.Tamamura, 他
  • Journal Title: J.Am.Chem.Soc. 132巻、45号 Pages: 15899-15901
  • Peer Reviewed
• [Journal Article] α,α-Dichloroisoxazolidinones for the synthesis and chemoselective peptide ligation of α-peptide α-ketoacids (2010)
  • Author(s): T.Narumi, J.W.Bode, 他
  • Journal Title: Heterocycles in press
  • Peer Reviewed
• [Journal Article] CD4 mimics targeting the HIV entry mechanism and their hybrid molecules with a CXCR4 antagonist (2010)
  • Author(s): T.Narumi, C.Ochiai, K.Yoshimura, S.Harada, T.Tanaka, W.Nomura, H.Arai, T.Ozaki, N.Ohashi, S.Matsushita, H.Tamamura, 他
  • Journal Title: Bioorg.Med.Chem.Lett. 20巻 Pages: 5853-5858
  • Peer Reviewed
• [Journal Article] Peptidic HIV integrase inhibitors derived from HIV gene products : structure-activity relationship studies (2010)
  • Author(s): S.Suzuki, K.Maddali, C.Hashimoto, E.Urano, N.Ohashi, T.Tanaka, T.Ozaki, H.Arai, H.Tsutsumi, T.Narumi, W.Nomura, N.Yamamoto, Y.Pommier, JA Komano, H.Tamamura, 他
  • Journal Title: Bioorg.Med.Chem. 18巻 Pages: 6771-6775
  • Peer Reviewed
• [Journal Article] Peptide HIV-1 Integrase Inhibitors from HIV-1 Gene Products (2010)
  • Author(s): S.Suzuki, E.Urano, C.Hashimoto, H.Tsutsumi, T.Nakahara, T.Tanaka, Y.Nakanishi, K.Maddali, Y.Han, M.Hamatake, K.Miyauchi, Y.Pommier, JA.Beutler, W.Sugiura, H.Fuji, T.Hoshino, K.Itotani, W.Nomura, T.Narumi, N.Yamamoto, JA.Komano, H.Tamamura, 他
  • Journal Title: J.Med.Chem. 53巻 Pages: 5356-5360
  • Peer Reviewed
• [Journal Article] Development of crosslink-type tag-probe pairs for fluorescent imaging of proteins (2010)
  • Author(s): W.Nomura, T.Mino, T.Narumi, N.Ohashi, A, Masuda, C.Hashimoto, H.Tsutsumi, H.Tamamura, 他
  • Journal Title: Biopolimers : Peptide Science 94巻 Pages: 843-852
  • Peer Reviewed
• [Journal Article] CD4 mimics targeting the mechanism of HIV entry (2010)
  • Author(s): Y.Yamada, C.Ochiai, K.Yoshimura, T.Tanaka, N.Ohashi, T.Narumi, W.Nomura, S.Harada, S.Matsushita, H.Tamamura
  • Journal Title: Bioorg.Med.Chem.Lett. 20巻 Pages: 354-358
  • Peer Reviewed
• [Journal Article] Remodeling of dynamic structures of HIV-1 envelope proteins leads to synthetic antigen molecules including neutralizing antibodies (2010)
  • Author(s): T.Nakahara, W.Nomura, K.Ohba, A.Ohya, T.Tanak, C.Hashimoto, T.Narumi, T.Murakami, N.Yamamoto, H.Tamamura, 他
  • Journal Title: Bioconjugate Chem. 21巻 Pages: 709-714
  • Peer Reviewed
• [Journal Article] Synthesis and biological evaluation of selective CXCR4 antagonists containing alkene dipeptide isosteres (2009)
  • Author(s): T.Narumi, R.Hayashi, K.Tomita, K.Kobayashi, N.Tanahara, H.Ohno, T.Naito, E.Kodama, M.Matsuoka, S.Oishi, N.Fujii, 他
  • Journal Title: Org.Biomol.Chem. Pages: 616-621
  • Peer Reviewed
• [Journal Article] Synthesis of protein kinase Cδ C1b domain by native chemical ligation methodology and characterization of its folding and ligand binding (2009)
  • Author(s): N.Ohashi, W.Nomura, M.Kato, T.Narumi, N.E.Lewin, P.M.Blumberg, H.Tamamura, 他
  • Journal Title: J.Pep.Sci. 15巻 Pages: 642-646
  • Peer Reviewed
• [Journal Article] Structure-activity relationship study on artificial CXCR4 ligand possessing the cyclic pentapeptide scaffold : the exploration of amino acid residues of pentapeptides by substitutions of several aromatic amino acids (2009)
  • Author(s): T.Tanaka, W.Nomura, T.Narumi, A.Esaka, S.Oishi, N.Ohashi, K.Itotani, B.J.Evans, Z.-X.Wang, S.C.Peiper, N.Fujii, H.Tamamura, 他
  • Journal Title: Org.Biomol.Chem. Pages: 3805-3809
  • Peer Reviewed
• [Journal Article] Peptide Bond Mimicry by (E)-Alkene and (Z)-Fluoroalkene Peptide Isosteres : Synthesis and Bioevaluation of α-Helical Anti-HIV Peptide Analogues (2009)
  • Author(s): S.Oishi, H.Kamitani, Y.Kodera, K.Watanabe, K.Kobayashi, T.Narumi, K.Tomita, H.Ohno, T.Naito, E.Kodama, M.Matsuoka, N.Fujii, 他
  • Journal Title: Org.Biomol.Chem. Pages: 2872-2877
  • Peer Reviewed
• [Journal Article] Amino Acid-Based Synthesis of Trifluoromethylalkene Dipeptide Isosteres by Alcohol-Assisted Nucleophilic Trifluoromethylation and Organozinc-Copper-Mediated S_N2' Alkylation (2009)
  • Author(s): K.Kobayashi, T.Narumi, S.Oishi, H.Ohno, N.Fujii, 他
  • Journal Title: J.Org.Chem. 74巻 Pages: 4626-4629
  • Peer Reviewed
• [Journal Article] Synthesis of Fluoroalkene Dipeptide Isosteres by an Intramolecular Redox Reaction Utilizing N-Heterocyclic Carbenes (NHCs) (2009)
  • Author(s): Y.Yamaki, A.Shigenaga, K.Tomita, T.Narumi, N.Fujii, A.Otaka, 他
  • Journal Title: J.Org.Chem. 74巻 Pages: 3272-3277
  • Peer Reviewed
• [Presentation] HIV-1外被タンパク質gp120の構造変化誘起を指向した低分子CD4ミミックの創製研究 (2011)
  • Author(s): 鳴海哲夫, 新井啓之、吉村和久、原田恵嘉、野村渉、松下修三、玉村啓和
  • Organizer: 日本薬学会第131年会(震災により中止)
  • Place of Presentation: 静岡
  • Year and Date: 20110328-20110331
• [Presentation] イミダゾリウム塩の構造最適化を指向した構造活性相関研究 (2011)
  • Author(s): 鳴海哲夫, 玉村啓和
  • Organizer: 日本薬学会第131年会(震災により中止)
  • Place of Presentation: 静岡
  • Year and Date: 20110328-20110331
• [Presentation] Bode JW. α,α-Dicholoroisoxazolidinones for The Synthesis and Chemoselective Peptide Ligation of α-Peptide α-Ketoacids. (2010)
  • Author(s): 鳴海哲夫
  • Organizer: 5th International Peptide Symposium.
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20101204-20101209
• [Presentation] HIV外被タンパク質gp120の構造変化誘起を指向した低分子CD4ミミックの創製 (2010)
  • Author(s): 鳴海哲夫, 新井啓之, 落合千裕, 尾崎太郎, 吉村和久, 原田恵嘉, 野村渉, 松下修三, 玉村啓和
  • Organizer: 第24回日本エイズ学会学術集会・総会
  • Place of Presentation: 東京
  • Year and Date: 20101124-20101126
• [Presentation] HIV-1外被タンパク質gp120の構造変化誘起を指向した低分子CD4ミミックの構造活性相関研究 (2010)
  • Author(s): 鳴海哲夫, 新井啓之, 落合千裕, 吉村和久, 原田恵嘉, 野村 渉, 松下修三, 玉村啓和
  • Organizer: 第29回メディシナルケミストリーシンポジウム
  • Place of Presentation: 京都
  • Year and Date: 20101117-20101119
• [Presentation] 有機銅試薬によるクロロアルケン型ジペプチドイソスターの合成研究 (2010)
  • Author(s): 鳴海哲夫, 清家俊輔, 尾崎太郎, 新井啓之, 野村渉, 玉村啓和
  • Organizer: 第36回反応と合成の進歩シンポジウム
  • Place of Presentation: 愛知
  • Year and Date: 20101101-20111102
• [Presentation] HIV侵入の動的超分子機構を模倣した立体構造特異的人工抗原分子の創製 (2010)
  • Author(s): 野村渉, 中原徹, 橋本知恵, 大庭賢二, 相馬晃, 田中智博, 鳴海哲夫, 山本直樹, 玉村啓和
  • Organizer: 第36回反応と合成の進歩シンポジウム
  • Place of Presentation: 愛知
  • Year and Date: 20101101-20101102
• [Presentation] Development of Small CD4 Mimic Molecules that Induce Conformational Changes in gp120. (2010)
  • Author(s): Arai H, Narumi T, Ochiai C, Yoshimura K, Harada S, Tanaka T, Nomura W, Ozaki T, Ohashi N, Matsushita S, Tamamura H
  • Organizer: 11th KUMAMOTO AIDS Seminer・GCOE Joint International Symposium.
  • Place of Presentation: Kumamoto, Japan
  • Year and Date: 20101006-20101008
• [Presentation] 新規アミド結合等価体の創製研究.クロロアルケン型ジペプチドイソスターの合成研究 (2010)
  • Author(s): 鳴海哲夫, 清家俊輔, 野村渉, 玉村啓和
  • Organizer: 日本ケミカルバイオロジー学会 第5回年会
  • Place of Presentation: 横浜
  • Year and Date: 20100518-20100519
• [Presentation] HIV-1外被タンパク質gp120の構造変化誘起を指向した低分子CD4ミミックの構造活性相関研究 (2010)
  • Author(s): 鳴海哲夫, 落合千裕, 山田裕子, 吉村和久, 原田恵嘉, 大橋南美, 野村渉, 松下修三, 玉村啓和
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 20100328-20100330
• [Presentation] 新規アミド結合等価体クロロアルケン型ジペプチドイソスターの合成研究 (2010)
  • Author(s): 鳴海哲夫, 清家俊輔, 野村渉, 玉村啓和
  • Organizer: 日本薬学会第130年会
  • Place of Presentation: 岡山
  • Year and Date: 20100328-20100330
• [Presentation] 新規アミド結合等価体クロロアルケン型ジペプチドイソスターの合成研究 (2010)
  • Author(s): 鳴海哲夫, 清家俊輔, 野村渉, 玉村啓和
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2010-10-02
• [Presentation] HIV外被タンパク質gp120の構造変化誘起を指向した低分子CD4ミミックの創製 (2010)
  • Author(s): 鳴海哲夫, 新井啓之, 落合千裕, 尾崎太郎, 吉村和久, 原田恵嘉, 野村渉, 松下修三, 玉村啓和
  • Organizer: 第54回日本薬学会関東支部大会
  • Place of Presentation: 東京
  • Year and Date: 2010-10-02
• [Presentation] Diastereoselective synthesis of (Z)-fluoroalkene dipeptide isosteres and their incorporation into the selective CXCR4 antagonists. (2009)
  • Author(s): Narumi T, Hayashi R, Tomita K, Kobayashi K, Tanahara N, Ohno H, Naito T, Kodama E, Matsuoka M, Nomura W, Tamamura H, Oishi S, Fujii N.
  • Organizer: The 3rd Asia-Pacific International Peptide Symposium.
  • Place of Presentation: Jeju Island, Korea
  • Year and Date: 20091108-20091111
• [Presentation] Development of CD4 mimic small molecules targeted for dynamic supramolecular mechanism of HIV entry. (2009)
  • Author(s): Ochiai C, Yoshimura K, Yamada Y, Tanaka T, Narumi T, Nomura W, Shibata J, Hatada M, Matsushita S, Tamamura H
  • Organizer: 第10回熊本エイズセミナー
  • Place of Presentation: 熊本
  • Year and Date: 20090928-20090929
• [Patent(Industrial Property Rights)] ケモカインレセプターCXCR4の二価型アンタゴニストの創製とがん細胞のイメージング方法の開発 (2009)
  • Inventor(s): 玉村啓和、野村渉、鳴海哲夫、田中智博
  • Industrial Property Rights Holder: 玉村啓和、野村渉、鳴海哲夫、田中智博
  • Industrial Property Number: 特許,特願2009-159771
  • Filing Date: 2009-07-06